Project Summary/Abstract Stiffness of the large elastic central arteries (e.g., aorta and carotids) increases with advancing age and is a robust predictor of incident cardiovascular disease (CVD) events among older adults. The age-related increase in central artery stiffness is associated with a concomitant rise in systolic blood pressure (BP) and pulse pressure (PP) and subsequently the development of isolated systolic hypertension (ISH) in many older adults. Consequently, higher PP results in greater pulsatile pressure and flow penetrating into high blood flow organs such as the brain causing subclinical target organ damage. Sympathetic nerve activity (SNA) also increases with advancing age and is associated with cardiovascular target organ damage including left ventricular hypertrophy and intima-medial thickness (IMT) of peripheral conduit arteries, but it remains unclear whether enhanced SNA modulates the age-related increase in central artery stiffness and associated augmented carotid pressure and flow pulsatility and increased IMT. Therefore, the objectives of this application are to 1) determine the contribution of SNA to the age-related increase in aortic stiffness and reduced carotid compliance, and augmented carotid pressure and flow pulsatility and IMT among older adults with ISH, and 2) determine the effectiveness of chronic inhibition of SNA for reducing large artery stiffness, carotid pressure and flow pulsatility and IMT among older adults with ISH. In Aim 1, we will enroll 30 older (age 60-85 years) adults (50% women/50% men) with untreated stage 1 or stage 2 ISH (systolic BP 130-159 mmHg; diastolic BP <90mmHg) in a repeated measures experimental study assessing aortic stiffness (carotid-femoral pulse wave velocity, PWV) and carotid artery compliance and pressure pulsatility index at baseline and during -15 and -30 mmHg of lower body negative pressure. We hypothesize that acute experimental elevations in SNA will result in transient increases in carotid-femoral PWV and decreases in carotid compliance resulting in higher carotid pressure and flow pulsatility. In Aim 2, we will enroll 78 healthy older men and women (age 60-85 years) with untreated or treated ISH in a randomized, placebo-controlled double blind study. We hypothesize that 4 weeks of chronic SNA inhibition with oral clonidine will result in clinically meaningful decreases in aortic stiffness and increases in carotid artery compliance, causing significant reductions in carotid pressure and flow pulsatility index and IMT. The proposed research will fundamentally advance our understanding of the regulation of large elastic artery stiffness by SNA among older humans with ISH, and provide valuable insight into SNA as a novel therapeutic target among older adults with ISH for lowering CVD risk.